Acute pain is characterized by a sudden onset and relatively short duration, and is generally treated with opioid analgesics like morphine. Morphine and similar opioid analgesics suppress the perception of pain by reducing the number of pain sensations sent by the nervous system and the brain's reaction to those pain signals. Current opioid therapy using morphine and like compounds are effective to treat pain but the side effects they produce such as addiction, somnolence, tolerance, respiratory depression, and constipation limit their clinical use.
In addition, opiates presently used in therapy such as morphine are alkaloid compounds isolated from natural sources such as the opium poppy. There are also semi-synthetic substances derived from the opium poppy, as well as and are chemically synthesized compounds including anilidopiperidines, phenylpiperidines, diphenylpropylamine derivatives, morphinan derivatives, and benzomorphan derivatives.
Opioid analgesics relieve pain and inhibit nociceptive signaling by binding to opioid receptors on cells in the central and peripheral nervous systems and the gastrointestinal tract. The analgesic effects of opioids are due to decreased perception of pain, decreased reaction to pain and increased resistance to pain. Known opioid receptors include mu (μ), delta (δ) and kappa (κ). Opioid receptor agonists, including morphine, the enkephalins, and the dynorphins, bind to these receptors. The most commonly studied opioid receptor modulated is the μ opioid receptor. However, kappa opioid receptor agonists have been shown to be effective and potent analgesics, but their usefulness in humans is limited due to their psychomimetic and dysphoric effects. Delta (δ) opioid receptor agonists are known to produce analgesic effects with lesser magnitude side effects than μ analgesics. For example, delta analgesics induce less tolerance and physical dependence, do not depress respiration, and cause few or no adverse gastrointestinal effects, including constipation. However, delta opioid receptor agonists can produce seizures. Moreover, in some animal experiments, delta opioid agonists can produce an effective and potent analgesic effect when administered intrathecally or by intracerebroventricular injection. However; these routes of administration are not practical for treating patients.
Therefore, there is still a need in the medical art to develop new treatments for pain which would facilitate patient therapy and reduce or eliminate unwanted side effects. Additionally, there is a need for the identification and development of new compounds and compositions that do not cross the blood-brain barrier and effectively alleviate pain without activating opioid receptors in the central nervous system.